Abstract
Azelastine, an anti-allergic agent, completely overcame the resistance to vincristine (VCR) of a VCR-resistant subline (P388/VCR) of P388 murine leukemia cells (P388). Considering our previous result [Yamamoto et al. (1989) J. Clin. Biochem. Nutr., 6, 205] that the drug overcame the resistance to adriamycin (ADM) of an ADM-resistant subline (P388/ADM) of P388, we concluded that the drug circumvents multidrug resistance of leukemia cells. This circumvention by azelastine is ascribable to the accumulation of anticancer agent in drug-resistant leukemia cells. As for the mechanism of the accumulation, a metabolic inhibition experiment showed that the accumulation is not due to increased influx of the drug into the cells but due to an azelastine-effected decrease in the efflux of the drug from the cells. Thus, the effect of azelastine on the binding of P-glycoprotein in plasma membrane fraction with VCR was examined. [3H] VCR binding to the membrane fraction prepared from an ADM-resistant human myelogenous leukemia cell line (K562/ADM) was inhibited by azelastine in a concentration-dependent manner. These results imply that azelastine circumvents multidrug resistance through, at least partly, the inhibition of the efflux of anti-cancer drug from leukemia cells by its binding to P-glycoprotein. We further noted that the treatment with azelastine in combination with VCR significantly prolonged the survival of P388/VCR-bearing mice as compared with those given VCR alone.
